Strategies for the control of crystal size and shape by mechanical action

Many pharmaceutical products are prepared as crystalline powders, where crystals have often needle-like shapes that are very difficult to process and to formulate as they are prone to entrain mother liquor, to flow badly and to form fines. Given the importance of particle size and shape on the product quality, different techniques, such as temperature cycles [1] and use of specific solvents or additives [2,3], have been investigated as possible approaches to manipulate crystal morphology. However, nedle-like particles are known to break rather easily when mechanical stress is applied. This stress can be applied through crystal-crystal, crystal-stirrer and crystal-reactor collisions. Crystal breakage and abrasion are usually unwanted in the production process due to the formation of fine particles that make downstream processes more challenging. However, applying mechanical stress in a controlled way, in example through wet milling, allows tuning the shape of crystals in a more rigorous way. In the pharmaceutical industry this is usually done after the crystallization step. This has the significant disadvantage that the broken particles are not processed anymore. Therefore, in this project, it is proposed to combine the three steps of crystallization, milling and heating in one single process. This has the advantage that small particles formed during the milling step can be dissolved by increasing the temperature in the crystallizer and that needle-like particles are broken into fragments, thus making them more compact after an additional growth phase. The scientific and technological challenges lie in the design, optimization and control of such a process and in developing it through an improved understanding of its theoretical aspects.
The project can be divide into two main branches, namely a characterization and a process development area. Concerning the characterization of the process, particular care will be dedicated to the description of the milling stage, combining a modeling and an experimental approach. The use of the in-house built flow-through cell [4] will allow to measure the particle size and shape distribution of the ground particles. The mathematical model developed to describe this stage, a morphological population balance equation, whose general formulation can be found elsewhere in literature [5], will be used in order to determine the kinetic parameters and the distribution of fragments formed after a breakage event in order to match the experimental evidence. Also the cooling and heating stages will be investigated in order to identify the best operating conditions maximizing the filterability and flowability of the final product.
Concerning the process development section of the project, the combined stages will be extended to an industrial application, starting from the design of the process that allows to selectively manipulate the size and shape of crystals to obtain compact particles. With the ongoing characterization activity outcome, the process configuration proposed will be updated to meet the requirements necessary to satisfy product specifications.